tbuckley/cabot-search huggingface dataset:
Abstract P3124: Chronic Infusion Of Angiotensin II Promotes Ventricular Fibrosis And Diastolic Dysfunction In Aging Male But Not Female Mouse Hearts
Authors: Manish Mishra, Ninh Khuong, Shubham Banga, Susan E Howlett
Journal: Circulation Research (2023)

Heart failure prevalence increases with age and affects men and women differently. Chronic activation of the renin-angiotensin system (RAS) in heart failure increases circulating angiotensin II (AII) levels, which elevates blood pressure (BP), promotes fibrosis and leads to adverse remodelling of the heart. Whether maladaptive responses to AII differ between the sexes at older ages is unclear, as most studies use young male animal models. We investigated whether adverse cardiac remodeling induced by chronic exposure to AII differed between the sexes in older C57BL/6 mice. Osmotic minipumps with pressor doses of AII (3 mg/kg/day) or saline were implanted into older mice (≈16 mos) of both sexes for 6 weeks. BP (tail cuff) and ventricular structure/function (echocardiography) were measured at baseline, midpoint, and endpoint. Ventricular fibrosis markers (transforming growth factor-ß (TGF-ß), fibronectin collagen I, collagen III) were quantified with qPCR. Mean arterial pressure increased similarly in both sexes (76.3±4.2 vs. 136.1±4.6 mmHg in males and 73.9±2.9 vs. 116.1±8.7 mmHg in females; p&lt;0.05; n=6-8/group). AII infusion also increased LV mass and reduced ejection fraction in males and females. By contrast, AII increased signs of diastolic dysfunction in males but had little impact on diastolic function in females. For example, isovolumic relaxation time increased over 6 weeks of AII infusion in males (11.7±1.0 vs. 19.0±1.4 ms; p&lt;0.05) but not in females (14.6±0.9 vs. 16.4±1.2 ms). Similar results were seen for E/A ratios. Molecular studies showed a marked increase in mRNA abundance for TGF-ß in male ventricles (1.02±0.13 vs. 1.50±0.16; p&lt;0.05) but not in females (1.01±0.08 vs. 1.25±0.10). Similar male-female differences were seen for collagens I and III (fibronectin was similar in both sexes, and not affected by AII). As TGF-ß signalling increases the production of profibrotic mediators like collagens I and III, these findings suggest that chronic RAS activation increases fibrosis and disrupts diastolic function in aging male hearts. By contrast, older female hearts are resistant to these deleterious effects of RAS activation. These sex-specific differences may modify heart failure expression and responses to treatment in older men and women.
Abstract P1180: Multi-scale Imaging And Analysis To Elucidate Cardiac Structure And Contractile Function
Authors: Yichen Ding, Milad Almasian, Xinyuan Zhang, Vinay Kadam, Jie Yuan
Journal: Circulation Research (2023)

Heart failure remains the leading cause of mortality worldwide, largely due to the lack of regenerative capacity of mature cardiomyocytes. The advanced understanding of cardiac architecture and function is critical to uncover the underlying mechanism of cardiac morphogenesis and the remodeling process in response to myocardial infarction. Recent progress has demonstrated that zebrafish and neonatal mice have the capacity to restore cardiac function following the injury, laying the foundation to investigate the cues to structural and functional abnormalities. For this reason, we have developed a light-sheet fluorescence microscope along with the tailored computational methods to investigate the 3-dimensional (3D) architecture of the intact mouse heart, and 4D (3D spatial + 1D temporal) cardiac contractility in zebrafish larvae. This method provides us ~ 2 um isotropic spatial resolution across the atria and ventricles with minimal photo-damage and maximal penetration depth. In combination with established tissue clearing methods, we are able to investigate myocardial trabeculation and compaction in mouse hearts within the 2-minute laser scanning. To unravel the contractile dysfunction following the anticancer therapy, we have coupled our imaging system with retrospective synchronization algorithm for the 4D reconstruction of myocardial deformation from end-systole to end-diastole in zebrafish hearts. To further interpret the deluge of 3D and 4D images, we have also developed a machine learning-based platform for interactive image analysis. Collectively, our multi-scale imaging strategy provides an entry point to assess micro-architecture and cardiac contractile function in the entire heart without physical slicing, holding the great potential to uncover the process of cardiac morphogenesis and regeneration.
Abstract P3016: Pathologic Matrix Markers Are Differentially Modulated By VSMC-Specific SGK-1 Activity In Hypertension And Abdominal Aortic Aneurysm
Authors: Victoria Mattia, Mario Figueroa, John Gedney, Ying xiong, Rupak Mukherjee, Jeffrey A Jones, Jean Marie Ruddy
Journal: Circulation Research (2023)

Introduction: The VSMC switch to synthetic phenotype promotes aortic pathology such as hypertension (HTN) and abdominal aortic aneurysm (AAA). Mechanical activation of serum and glucocorticoid inducible kinase-1 (SGK-1) alters the VSMC synthetic profile to promote remodeling. Plasma biomarkers may represent opportunities to assess VSMC function in aortic disease, and we hypothesize that analysis of a panel of plasma pathologic matrix markers (PMM) representing synthetic VSMC phenotype can reflect SGK-1-dependent activity. Methods: HTN was induced in wild-type C57Bl/6 (WT) and smooth muscle cell specific SGK-1 knockout (SMC-SGK-1KO +/- ) mice with AngiotensinII infusion (1.46mg/kg/day, n=4-6). Separate mice underwent AAA induction by peri-adventitial CaCl 2 application (n=4-6). Terminal procedure included collecting systolic blood pressure (SBP), aortic diameter (AoD), and plasma. ELISA for PMMs included Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Cathepsin S (CtsS), and Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). Impact of the panel was evaluated by a composite T-score. Statistics included T-test and ANOVA. Results: WT+HTN had &gt;30% increased SBP and elevation of IL-6, CtsS, CysC, and TNC (p&lt;0.05). SMC-SGK-1KO +/- +HTN had equally elevated SBP, but no change in PMMs, suggesting that SGK-1 contributed to HTN-induced VSMC synthetic activity. WT+AAA had &gt;65% increased AoD and elevation of all PMMs (p&lt;0.05). Alternatively, SMC-SGK-1KO +/- +AAA had abrogated growth (29.4 + 3.6%, p&lt;0.05 vs WT and WT+AAA) with IL-6, CtsS, CysC, and TNC returning to baseline, suggesting that SGK-1-dependent production of these PMMS was necessary for true AAA growth. Composite T-scores differed between Control, HTN, and AAA in WT mice (0.78 + 0.08 vs 2.91 + 0.29 vs 7.11 + 0.71 respectively, p&lt;0.05). In SMC-SGK-1KO +/- mice, T-score normalized in HTN but remained elevated in AAA (2.19 + 0.21, p&lt;0.05 vs Control and WT+AAA), attributable to the elevations in MMP-9 and OPG, peptides produced by inflammatory infiltrate. Conclusion: A panel of PMMs can be scored to reflect synthetic activity of VSMCs in aortic pathology, as well as response to inhibition, and warrants further investigation for the clinical care of patients with vascular disease.
Abstract P3011: Assessing Subclinical Atherosclerosis Using Carotid Intima-media Thickness In Inflammatory Bowel Disease Patients: A Metanalysis
Authors: Vagisha Sharma, ASHOK JAGDISH BHASKAR, Syeda Fatima Murtaza, Syed Asjad Tauheed Zaidi, Mayank Dineshbhai Kamani, Ritika Behera, Sohmika Wadhwa, Muskaan Sutaria, Vijaya Rupa Konakanchi, Advait Joshi, Ritwik Roy, Advait Vasavada
Journal: Circulation Research (2023)

Objective: Chronic inflammatory diseases are linked to atherosclerosis and cardiovascular events. However, there are conflicting results published in the literature regarding differences in carotid intima-media thickness, a marker of subclinical atherosclerosis, between inflammatory bowel disease patients and controls. We aimed to conduct a pooled analysis of the studies and determine if it is true. Method: We performed a systematic literature search of databases Google Scholar, Scopus and PubMed from Jan 01, 2012, until Feb 01, 2023. Unadjusted odds ratios (OR) were pooled using a random-effect model, and a p-value of &lt;0.05 was considered statistically significant. Findings: A total of 4 studies with 354 participants were shortlisted for analysis. The results shown in the figure show an insignificant difference in the carotid intima-media thickness between inflammatory bowel disease patients and control groups of healthy individuals - the odds ratio came out -0.22 with a confidence interval of -0.89 to 0.45 and p-value of &lt;0.05. Conclusions: Our pooled analysis revealed no impact of IBD on carotid-intima media thickness. Future studies should focus on scrutinizing the actual risk of atherosclerosis and its complications with the disease.
Abstract P3137: The C-terminus Of Rad Is Required For Regulation Of The Cardiac Ca <sub>V</sub> 1.2 Channel
Authors: Garrett Elmore, Brooke M Ahern, Andrea Sebastian, Sarisha Lohano, Nicholas McVay, Bryana Levitan, Alec Dupont, Doug A Andres, Jonathan Satin
Journal: Circulation Research (2023)

Background: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and death. Current therapies fail to address loss of contractile force. Targeting dysfunctional Ca 2+ handling proteins involved in excitation-contraction, such as Ca v 1.2 may offer a means to improve quality of life and attenuate adverse cardiac remodeling. RAD is a key target bridging sympathetic modulation of Ca v 1.2 function. During stress, the beta-adrenergic (β-AR) effector, protein kinase A (PKA), phosphorylates RAD, modulating Ca v 1.2 current (I Ca,L ) and increasing cardiac contraction. RAD inhibits current, whereas Rad-knockout phenocopies a β-AR/PKA phosphorylated modulated current. Across RGK family members the highly conserved C-terminus is necessary for membrane association and block of I Ca,L in immortalized cell lines. The RAD C-terminus significance is unknown in adult mammalian cardiomyocytes. Hypothesis: RAD lacking a C-terminus will be unable to localize to surface membrane Ca v 1.2 channels; thus Ca v 1.2 activity will be modulated. Methods and Results: A 3xFLAG epitope was added to the N-terminus of the endogenous mouse Rrad gene. Full-length FLAG-RAD mice were compared to mice with truncated RAD (A277X). Ventricular cardiomyocytes were isolated for immunocytochemistry and ex vivo electrophysiology. Confocal microscopy was used to visualize localization of FLAG-tagged RAD. Full-length FLAG-RAD showed a repeating t-tubular pattern that co-localizes with Ca v 1.2 staining whereas FLAG-RAD A277X failed to show this pattern. A277X I Ca,L showed significantly hyperpolarized activation midpoint (-17 mV) and 2-fold increase in maximal conductance. Additionally, current decay was faster in A277X showing a significant 2-fold decrease in the current 30 ms after peak current. Conclusions: Myocardial Ca v 1.2 channels in a RAD C-terminal deletion model phenocopy Ca v 1.2 function modulated in response to β-AR stimulation. Mechanistically, the polybasic RAD C-terminus confers Ca v 1.2 regulation via membrane association of RAD. Interfering with RAD at the C-terminus residues constitute a specific target for boosting heart function as a treatment for HFrEF.
Abstract P3002: Role Of Vascular Fibroblast Growth Factor Signaling In Group 3 Hypoxia-induced Pulmonary Hypertension
Authors: Kel Vin Woo, Carla Weinheimer, Jess Nigro, Attila Kovacs, David Ornitz
Journal: Circulation Research (2023)

Pulmonary hypertension (PH) is a debilitating disease characterized by pathologic changes in the pulmonary vasculature that increases pulmonary vascular resistance and leads to right heart failure. Group 3 PH is caused by lung disease and/or hypoxia, including bronchopulmonary dysplasia (BPD) and chronic obstructive lung disease (COPD), and is the second largest cause of mortality in PH patients. PH further increases the morbidity and mortality in both COPD and BPD patients. Fibroblast Growth Factor 2 (FGF2) and FGF Receptor 1 (FGFR1) expression is elevated in lung tissue of PH patients. To study the role of FGF signaling in the pathogenesis of group 3 PH, we developed a physiologically relevant mouse model in which mice are challenged with 10% hypoxia for 2 weeks. Following hypoxia exposure, cardiac catheterization is used to measure right ventricular (RV) pressure that mimics Group 3 PH. Lung tissue is then analyzed for histological and molecular changes. Our initial work showed that inactivation of FGFRs in endothelial cells (EC) worsened hypoxia-induced PH while expression of a constitutively active FGFR1 (caFGFR1) in ECs protected against hypoxia-induced PH. Here we hypothesize that FGF signaling may also affect the pathogenic response to hypoxia of vascular smooth muscle (VSMC), potentially by limiting vascular muscularization in response to hypoxia. We show that in vitro inhibition of FGF2 signaling in human pulmonary artery VSMCs reduced hypoxia-induced proliferation while promoting a contractile phenotype, and in vivo inactivation of FGFRs 1 and 2 worsened hypoxia-induced vascular remodeling. These data suggest the potential for a dual beneficial effect of activation of FGF signaling, both in regulating EC-VSMC interactions and directly preventing VSMC remodeling.
Abstract P3132: Tgfβ Signaling Triggers Nonmyocyte Gene Expression In Tbx18-induced Pacemaker Myocytes And Abbreviates Their Automaticity
Authors: Jinqi Fan, Hee Cheol Cho
Journal: Circulation Research (2023)

Background: We have previously demonstrated reprogramming of ventricular myocytes into induced pacemaker cells (iPMs) using an embryonic transcription factor TBX18. We have also discovered that Tgfβ pathway is significantly upregulated in TBX18-iPMs, and triggers fibrosis upon gene transfer in vitro and in vivo. Here, we sought to investigate the impact of Tgfβ signaling on iPMs’ automaticity. Methods: Neonatal rat ventricular myocytes (NRVMs) were transduced with Adeno-TBX18 or control Adeno-GFP. Single cell RNAseq was performed at days 3, 6, and 14. Spontaneous field potentials from NRVM monolayers were recorded with microelectrode array. Results: TBX18 gene transfer strongly repressed working cardiomyocyte gene expression, e.g., Gja1, Scn5a, Pln throughout the 14-day period. TBX18-NRVMs progressed toward pacemaker cells, evidenced by increase in nodal pacemaker-related ion channel gene expression. TBX18 also triggered cytoskeletal remodeling, and activated nonmyocyte gene expression throughout the 2-week window. This was illustrated by ECM remodeling gene expression such as Acta2, Col1a1, and Postn. Treatment with A83-01, a small molecule inhibitor of Tgfβ receptors, mitigated the increase in nonmyocyte gene expression. TBX18-NRVMs exhibited spontaneously oscillating field potentials, reaching a peak pacing frequency of 196±36 bpm during week 1, which is comparable to the sinus rhythm of newborn rats. However, the pacing frequency gradually wavered after week 1. In contrast, A83-01-treated TBX18-iPMs showed peak pacing frequency beyond week 1, with the majority of their total beat counts near their sinus rhythm (63.3%) while only 14.9% of total beats were near the sinus rhythm in TBX18-iPMs without Tgfβ inhibition (P&lt;0.001). Interestingly, A83-01 did not impact PM-related ion channel gene expression (such as Hcn4, Gjc1) nor the percentage of TBX18-iPMs (5.1% vs. 5.4%, with or without A83-01, p=0.561), suggesting that improved automaticity may be due to its impact on nonmyocytes. Conclusion: TBX18-iPMs exhibit increased Tgfβ signaling and nonmyocyte gene expression, which negatively impacts their automaticity. Inhibition of Tgfβ signaling modulates nonmyocyte gene expression and enhances automaticity of TBX18-iPMs.
Abstract P1065: Primitive Macrophages Enhance The Function Of Bioengineered Human Cardiac Microtissues
Authors: Homaira Hamidzada, Simon Pascual-Gil, Michael A Laflamme, Gordon Keller, Milica Radisic, Slava Epelman
Journal: Circulation Research (2023)

Human cardiac bioengineering has traditionally focused on cardiomyocyte differentiation and maturation. Unlike normal cardiac growth in the native human heart, human pluripotent stem cell (hPSC)- derived cardiomyocytes are typically grown in the absence of key supportive populations, which may negatively impact function due to a failure to recreate complex multicellular environments. In vivo murine studies have demonstrated that embryonic-derived resident cardiac macrophages promote neonatal cardiac regeneration, yet macrophages have not been incorporated in cardiac bioengineering approaches. We hypothesized that inclusion of human embryonic stem cell derived primitive macrophages (hESC-macrophages) into bioengineered human cardiac microtissues (“Biowires”) would improve cardiomyocyte functional properties. We found that addition of hESC-macrophages into Biowires led to enhanced contractile force, improved relaxation, reduced excitation threshold, increased maximum capture rate, and increased conduction velocity that mechanistically was correlated with improved calcium cycling, indicating hESC-macrophages improve a broad range of electromechanical properties. Moreover, hESC-macrophages enhanced microtissue function across cardiomyocyte cell sources and bioengineering platforms (Experimental N=6 independent cellular differentiations across 2 different platforms). These changes occurred in the absence of significant transcriptional shifts in cardiomyocytes. Rather, Biowires with hESC-macrophages had reduced mitochondrial DNA release, oxidative stress and cytotoxicity in the very early phases of tissue formation, thereby promoting a favorable environment for cardiac microtissue development. In conclusion, these data reveal a previously unappreciated, yet major beneficial role for macrophages specifically in human cardiac tissue engineering. In general, bioengineering human tissue continues to be a major research focus, and our data argue that inclusion of yolk sac-derived macrophages may improve early microtissue formation and modeling in vitro , and could enhance cell delivery approaches in vivo .
Abstract P3001: Regulation Of Perivascular Adipose Tissue By Follistatin In Hypertension
Authors: Ann Kuganathan, Marcos Leal, Vincent Lu, Melissa MacDonald, Bo Gao, Jeffrey Dickhout, Joan Krepinsky
Journal: Circulation Research (2023)

Follistatin lowers BP and improves resistance artery health in spontaneously hypertensive rats (SHR), a model of essential HTN. Functionally, follistatin improves smooth muscle contraction and endothelium-dependent relaxation. Structurally, increased medial collagen was inhibited. Vascular ROS were also reduced. Perivascular adipose tissue (PVAT) regulates vascular tone via release of vasoactive substances. Oxidative stress in PVAT, as in HTN, induces release of contractile agents. Transition from white to brown PVAT is associated with decreased risk of CVD. We analyze effects of follistatin on PVAT and its regulation of vessel function in SHR and normotensive Wistar Kyoto (WKY) rats. White and brown PVAT were dissected from treated rats; arteries were isolated from untreated donors. PVAT was introduced near strain-matched donor arteries and assessed for ROS levels and contractility using DHE and wire myography, respectively. In some vessels, endothelium was denuded to assess its contribution to contraction. Follistatin reduced ROS, hypercontractility, and improved relaxation in a PVAT-dependent manner. Brown PVAT induced significant anti-contractile and antioxidant effects. Elevated expression of adipose tissue browning markers and decreased adipocyte area with follistatin, support PVAT browning effects. Endothelium removal results in augmented vessel constriction, effects reduced by follistatin. Follistatin improves SHR smooth muscle tone in a PVAT-dependent manner, likely through the inhibition of vascular ROS and browning of PVAT. Future work will profile PVAT effects of follistatin through unbiased proteomic analysis. Although most vessels are surrounded by PVAT, studies of PVAT-vessel interaction in HTN are few. By characterizing PVAT dysfunction, we aim to outline specific PVAT-mediated pathways involved in lowering BP and improving vascular function and structure. Results will provide new insights into PVAT-targeted therapy for essential HTN, allowing potential translation of benefits to obesity and other diseases exhibiting PVAT dysfunction.
Abstract P3004: Vaccination Targets Senescence-associated Glycoprotein Ameliorates Alzheimer’s Pathology And Cognitive Behavior In Mice
Authors: Chieh Lun Hsiao, Goro Katsuumi, Masayoshi Suda, Ippei Shimizu, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Ryo Furuuchi, Yung-ting Hsiao, Jia-Qi Liang, Manabu Abe, Tohru Minamino
Journal: Circulation Research (2023)

Introduction: From the patients and the mice with atherosclerosis, we found senescence-associated glycoprotein (SAGP-protein) was upregulated in macrophage and vascular endothelial cells. Analysis of transcriptome data from human vascular endothelial cells (HUVECs) revealed the enrichment of SAGP-protein in the HUVECs with senescent status. Based on molecular targeting strategy, we have developed a senolytic vaccine (SAGP-vaccine), which could eliminate SAGP-high senescent cells, leading to amelioration of age-associated pathologic condition including diabetes and atherosclerosis in mice. Since previous studies have reported the positive correlation between SAGP-protein and another age-associated disorder, Alzheimer’s disease (AD), we hypothesize that SAGP-vaccine would also be a treatment to AD. Purpose: This study was aimed to examine the efficacy of SAGP-vaccine in improving AD pathology and degeneration in AD mouse model. Methods: Mice with knock-in of human mutant amyloid precursor protein (APP NL-G-F ) (APP-KI) were treated with control vaccine or SAGP-vaccine at 2 and 4 months old. Behavior tests were performed from 6 months old, and sacrificed afterwards. Brain samples were harvested for further molecular-biological analysis. Results: APP-KI mice with SAGP-vaccination showed the significant improvement in behavior tests along with the reduction of SAGP expression and APP deposition in brain tissue. Furthermore, SAGP-vaccination significantly reduced expression of inflammatory molecules. Consist with previous studies, SAGP was mainly colocalized with microglia, which is the possible target of SAGP-vaccine. Conclusions: SAGP-vaccine would be a sufficient treatment to alleviate amyloid beta-induced pathogenesis in the brain and mitigate the impaired behaviors of AD.